This application, entitled, Interdisciplinary Investigation of Biological Signatures of Autism Subtypes is in response to RFA-MH-09-170 titled, Recovery Act Limited Competition: Research to Address the Heterogeneity of Autism Spectrum Disorders (R01). There is near universal agreement that there are multiple biological subtypes of autism and each of these types may have a quite distinct etiology. A major roadblock to understanding the causes of the different types of autism, and ultimately to identifying preventions or best treatments for each type, is that there is currently no way to distinguish and parse one type of autism from another at diagnosis. What is the best strategy to deal with the heterogeneity of ASD? This application proposes to study a very large cohort of children with autism spectrum disorders (ASD) using a multidisciplinary analytic approach in order to identify biological signatures that define distinct phenotypes of autism. The proposal is an extension of a pilot project initiated at the M.I.N.D Institute called the Autism Phenome Project (APP). One hundred sixty preschoolers with ASD and with typical development (TD) have already received full medical evaluation, medical record review, environmental exposure assessment;blood based genetic and immune profiling, structural magnetic resonance imaging, EEG based studies of auditory processing and comprehensive developmental and neuropsychological evaluations. We have established, therefore, that the intensive bio-behavioral studies proposed in this project are entirely feasible. Moreover, preliminary data from the APP have already highlighted at least three biological signatures of autism phenotypes. These include: (1) the presence of auto antibodies to GABAergic neurons which are observed in 21% of ASD children and 0% of TD (maternal antibodies and cytokine profiles are additional putative immune biosignatures);(2) abnormal auditory evoked potential responses (4 distinct response profiles have been observed) and (3) abnormal brain size (evidence is accumulating for both enlarged and small brains and frontal lobes). Having accomplished the pilot phase of this project and obtaining assurance that all procedures are feasible and well tolerated, we are ready to complete Phase 1 of this project. This will complete ongoing recruitment of 250 children with autism and 150 age-matched controls. This is a sufficiently large number to realistically expect to identify several subtypes of autism. All children will undergo the comprehensive multidisciplinary analyses described previously. Blood samples, DNA and RNA will be banked for future studies. We will establish a new data management and biostatistician group to organize and analyze data and transfer it to NDAR. Not only will this research program accomplish a unique, in depth analysis of a very large cohort of young children with autism and age-matched controls, but it will also provide the substrate for future longitudinal studies aimed at determining how early biological signatures of autism predict subsequent behavioral, biological and medical outcomes. It will also foster effective prevention and treatment research. PUBLIC HEALTH RELEVANCE: Autism is a neurodevelopment disorder that occurs in as many as 1 in 150 children and a major roadblock to preventing and more adequately treating autism is that there are many causes and many types. It is currently impossible to determine what type of autism a child has at diagnosis so in order to solve this problem;we will study the biology of a large number of children with autism to identify biological signatures of different types of autism. We already have strong evidence for at least an autoimmune type of autism and this research will lead to more effective efforts at preventing future cases of autism and treating existing children with autism.